title: Primacy of angiotensin converting enzyme in angiotensin-(1-12) metabolism.
abstract: Angiotensin-(1-12) [ANG-(1-12)], a new member of the renin-angiotensin system, is recognized as a renin independent precursor for ANG II. However, the processing of ANG-(1-12) in the circulation in vivo is not fully established. We examined the effect of angiotensin converting enzyme (ACE) and chymase inhibition on angiotensin peptides formation during an intravenous infusion of ANG-(1-12) in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). WKY and SHR were assigned to a short ANG-(1-12) infusion lasting 5, 15, 30, or 60 min (n = 4-10 each group). In another experiment WKY and SHR were assigned to a continuous 15-min ANG-(1-12) infusion with pretreatment of saline, lisinopril (10 mg/kg), or chymostatin (10 mg/kg) (n = 7-13 each group). Saline or lisinopril were infused intravenously 15 min before the administration of ANG-(1-12) (2 nmol·kg(-1)·min(-1)), whereas chymostatin was given by bolus intraperitoneal injection 30 min before ANG-(1-12). Infusion of ANG-(1-12) increased arterial pressure and plasma ANG-(1-12), ANG I, ANG II, and ANG-(1-7) levels in WKY and SHR. Pretreatment with lisinopril caused increase in ANG-(1-12) and ANG I and large decreases in ANG II compared with the other two groups in both strains. Pretreatment of chymostatin had no effect on ANG-(1-12), ANG I, and ANG II levels in both strains, whereas it increased ANG-(1-7) levels in WKY. We conclude that ACE acts as the primary enzyme for the conversion of ANG-(1-12) to smaller angiotensin peptides in the circulation of WKY and SHR and that chymase may be an ANG-(1-7) degrading enzyme.
authors.affiliation: Division of Surgical Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina;
authors.forename: Norihito
authors.initials: N
authors.lastname: Moniwa
authors.forename: Jasmina
authors.initials: J
authors.lastname: Varagic
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Simington
authors.forename: Sarfaraz
authors.initials: S
authors.lastname: Ahmad
authors.forename: Sayaka
authors.initials: S
authors.lastname: Nagata
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Voncannon
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
mesh_terms: D000803:Angiotensin I / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D053818:Chymases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007262:Infusions, Intravenous; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; C515557:proangiotensin-12, rat; D000808:Angiotensinogen; D000803:Angiotensin I; C002101:chymostatin; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; D053818:Chymases; C118790:angiotensin I (1-7)
keywords: angiotensin I; angiotensin II; angiotensin converting enzyme; angiotensin-(1–12); angiotensin-(1–7); blood pressure; chymase; hypertension